The present invention relates to certain deaza ring compounds. Compounds of the present invention are especially suitable as inhibitors of purine nucleoside phosphorylase (PNP). The present invention also relates to pharmaceutical compositions comprising the composition of the present invention, as well as methods of using the compounds in inhibiting PNP and in inhibiting T-cell proliferation in a mammal. The present invention also relates to treating cancer in a mammal.
The present invention also relates to a method for producing the compounds of the present invention.
The enzyme purine nucleoside phosphorylase (PNP) catalyses the reversible cleavage of purine nucleosides to the purine base and ribose-1-phosphate. Several cases of a rare genetic disorder in which PNP is lacking have been reported in children. These children are found to be T-cell immunodeficient while their B-cell immunity remained normal. This observation helped establish the relationship between PNP and T-cells and provided the impetus for the development of inhibitors of PNP which may be useful for the treatment of T-cell proliferative disorders. PNP functions as a salvage enzyme in the purine pathway. It is responsible for the reversible phosphorolysis of the ribonucleotides and 2xe2x80x2-deoxyribonucleotides of guanine, hypoxanthine, and related nucleotides to the free base and the phosphorylated sugar. Within intact cells, PNP normally acts in the phosphorolytic direction since the 6-oxopurines are further metabolized.
In children with enzyme deficiency, there is a low uric acid concentration since hypoxanthine and guanine catabolism is shut off and there are high inosine, guanosine, 2xe2x80x2-deoxyinosine, and dGuo nucleoside levels in plasma and urine. From the elevated nucleoside pool, only the elevated levels of dGuo have an inhibitory effect on T-cells. The elevated levels and dGuo become rapidly phosphorylated within these cells to 2xe2x80x2-deoxyguanosine monophosphate (dGMP) by their high level of 2xe2x80x2-deoxycytidine kinase (dCK). dGMP is further phosphorylated to its triphosphate (dGTP), which, in turn, shuts off DNA synthesis, preventing T-cell proliferation and eventually resulting in cell death. Only proliferating T-cells are impaired by this mechanism.
Accordingly, it would be desirable to develop a potent PNP inhibitor.
The present invention relates to certain pyrrolidine compounds and particularly to compounds represented by the following formula: 
wherein A is selected from the group consisting of 
W is NH2 or H; each X, Y and Z independently is selected from the groups consisting of HOH and halogen provided that at least one of X and Y is H; tautomers, and pharmaceutically acceptable salts thereof.
Another aspect of the present invention relates to pharmaceutical compositions containing at least one of the above-disclosed compounds.
The present invention also relates to a method for suppressing purine nucleoside phosphorylase in a patient by administering to the patient at least one of the above-disclosed compounds in an amount sufficient to suppress purine nucleoside phosphorylase.
A still further aspect of the present invention relates to suppressing T-cell proliferation by administering to a patient at least one of the above-disclosed compounds in an amount sufficient to suppress T-cell proliferation.
The present invention is also concerned with methods of using the compounds of the present invention in treating cancer is a mammal.
Still further aspects of the present invention are concerned with preparing the above-disclosed compounds. In particular, compounds wherein A is represented by formula 1 above can be prepared as follows:
1. Converting 3,9-dideaza hypoxanthine (7) to the corresponding 6-chloro compound;
2. Protecting the NH group with a blocking compound;
3. Replacing the 6-chloro group with an alkoxy group;
4. Brominating the compound from step 3 to provide the corresponding bromo compound;
5. Reacting the compound from step 4 with an alkyl lithium compound to replace the bromo group with a lithium group; or forming a Grignard of the bromo compound from step 4;
6. Condensing the compound from step 5 with 5-O-t-butyldimethyl-silyl-1, N-dehydro-1,4-dioxy, 1,4-imino-2,3-O-isopropylidene-D-ribitol;
7. Deprotecting the compound from step 6 under acidic conditions to provide the target compound.
The azasugar and analogs thereof can be obtained by known methods such as described in PCT WO 99/19338 to Furneaux et al.
In addition, compounds wherein A is represented by formula 1 can be prepared as follows:
1xe2x80x2. Reacting 2-chloro-4-methyl-3-nitropyridine with methylene to give the corresponding methoxide compound;
2xe2x80x2. Condensing the methyl group with dimethyl-formamide dimethyl acetal to give the corresponding enamine;
3xe2x80x2. Hydrogenating the compound from step 3;
4xe2x80x2. Protecting the NH group with a blocking compound; and
5xe2x80x2. Hydrogenating the compound from step 4 to provide the corresponding bromo compound; and continuing with steps 5-7 discussed above.
Compounds wherein A is presented by formula 2, can be prepared as follows:
1. Nitrating 3-methyl-5-nitrophenol to provide the corresponding dinitrophenol compound;
2. Condensing the methyl group of this compound from step 1 with dimethylformaldehyde dimethyl acetal;
3. Hydrogenating the compound from step 2 to cyclize it;
4. Protecting the hydrogen groups with blocking groups;
5. Bromonating the compound from step 4 to provide the corresponding bromo compound;
6. Reacting the compound from step 5 with an alkyl lithium compound to replace the bromo group with a lithium group forming an anion of the bromo compound from step 5;
7. Condensing the compound from step 6 with 5-O-t-butyldimethyl silyl-1, N-dehydro-1,4-dideoxy 1,4-imino -2,3,-O-isopropylidene-D-ribitol.
8. Deprotecting the compound from 7 under acidic conditions to provide the target compound.
Compound wherein A is represented by formula 3 can be prepared as follows:
1. Condensing 2-aminoacetaldehyde and ethyl-3-cyano-2-oxopropanate to form a pyrrole;
2. Protecting the hydrogen with a blocking compound;
3. Hydrolysing the compound from step 2 to form the corresponding acid compound;
4. Converting the acid compound from step 3 to the corresponding acid halide;
5. Reacting the compound from step 4 with an alkyl lithium compound to form the corresponding ketone;
6. Reacting the ketone from step 5 with lithium diisopropylamide (LDA).
7. Reacting the product from step 6 with TMSCl to provide the corresponding enolate;
8. Reducing the compound from step 7 to provide to corresponding amino-methyl compound.
9. Reacting the compound from step 8 with Bromine to cyclize it;
10. Converting the compound from step 9 to a ketal;
11. Reacting the compound from step 1 with chloromethyl benzyl ether (BOMCl);
12. brominating the compound from step 11;
13. Reacting the compound from step 12 with an alkyl lithium compound to replace the bromo groups with a lithium group, or forming a Grignard of the bromo compound from step 12;
14. Condensing to compound from step 13 with 5-O-t butyl dimethyl-silyl-1,N-dehydro-1,4-dideoxy 1,4-imino-2,3-O-isopropylidene-D-ribitol; and
15. Deprotecting the compound from step 14 under acidic conditions to provide the target compound.
Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described preferred embodiments of the invention, simply by illustration of the best mode contemplated of carrying out the invention. As will be realized the invention is capable of other and different embodiments, and it""s several details are capable of modifications in various obvious respects, without departing from the invention. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.